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Autosomal recessive disorders among patients attending the genetics
clinic in Alexandria
Volume 4, Issue 3, 1998, Page 470-479
M.M. Mokhtar, S.M. Kotb and S.R. Ismail
ABSTRACT A total of 660 patients referred to the genetics clinic, Medical Research Institute,
Alexandria were assessed to determine the frequency of genetic disorders and the proportion
of autosomal recessive disorders. It was found that 298 (45.2%) patients had genetic
disorders, 100 (33.6%) of whom had an autosomal recessive disorder; these included 32
patients with metabolic defects, 18 with haemoglobinopathies and 50 with syndromes and
single defects. The frequency of consanguinity among parents of patients with autosomal
recessive disorders was high (60%, with 48% first cousins). The average inbreeding
coefficient was higher (0.03) than that reported for the Egyptian population in general (0.01).
Maladies autosomiques récessives chez des patients consultant dans un service de
génétique à Alexandrie
REsumE Un nombre total de 660 patients qui avaient été orientés vers le service de
génétique de l'Institut de Recherche médicale d'Alexandrie a fait l'objet d'une évaluation
visant à déterminer la fréquence des maladies génétiques et la proportion des maladies
autosomiques récessives. On a constaté que 298 patients (45,2%) présentaient des maladies
génétiques dont 100 (33,6%) une maladie autosomique récessive; parmi ces derniers, 32
patients avaient des anomalies du métabolisme, 18 des hémoglobinopathies et 50 des
syndromes ou des anomalies simples. La fréquence de la consanguinité chez les parents des
patients présentant des maladies autosomiques récessives était élevée (60%, avec 48% de
cousins germains). Le coefficient de consanguinité moyen était plus élevé (0,03) que celui
rapporté pour la population égyptienne en général (0,01).
Introduction
It is a useful concept to consider all diseases as being on a spectrum. At one extreme we
have those disorders which are largely environmental in cause; at the other extreme we have
those disorders which are largely genetic [1].
A number of surveys have indicated that globally at least 2 per 1000 neonates have
autosomal recessive disorders, 2-10 per 1000 have autosomal dominant disorders, 1-2 per
1000 have X-linked recessive disorders, 6-7 per 1000 have chromosomal abnormalities and
about 20 per 1000 have congenital malformations [2].
A recent publication on genetic disorders among Arab populations lists 115 new genetic
syndromes reported over the past two decades. Of these, 100 syndromes are autosomal
recessive, 10 are autosomal dominant and 5 possibly X-linked recessive or autosomal
recessive [3].
Autosomal recessive disorders are generally severe; many inborn errors of metabolism and
malformation syndromes are due to autosomal recessive genes and their recognition in the
first affected individual in a family is of great importance as the recurrence risks are often high
and the disorders are frequently untreatable [2].
Recessively inherited disorders account for a substantial proportion of mental and physical
handicaps in some countries. Similarly, children of consanguineous parents may be
overrepresented in patients with severe mental retardation, blindness, hearing impairment
and deaf-mutism [3].
The aims of this work were to obtain baseline information on the frequency of genetic
disorders among a group of patients attending the genetics clinic of the Medical Research
Institute, Alexandria University, to classify and estimate the proportion of autosomal recessive
disorders and to determine the relationship between the disorders diagnosed and the
inbreeding coefficient.
Patients and methods
The study included all patients (660) attending the human genetics clinic of the Medical
Research Institute, Alexandria University, during the two-year period, 1995 and 1996. They
were referred from paediatric hospitals and private clinics and the reasons for the referrals are
given in Table 1. Accurate diagnosis was made after the following had been carried out:
taking of the complete genetic and family history, pedigree construction, clinical genetic
examination and anthropometric measurements. Other investigations were carried out
depending on the individual patient, such as skeletal survey, ultrasound,
electroencephalogram, hearing tests and fundus examination. Laboratory studies were
carried out as appropriate and included biochemical screening tests and thin-layer
chromatography, determination of haemoglobin level and red cell morphology, absolute red
cell indices, haemoglobin electrophoresis, chromosomal analysis, consanguinity and
inbreeding coefficient evaluation.
Results
Genetic disorders
Of the 660 patients, genetic disorders were detected in 298 (45.2%); of these 100 (33.6%)
had autosomal recessive disorders, 40 (13.4%) had autosomal dominant disorders, 20 (6.7%)
had X-linked disorders, 15 (5.0%) had multifactorial disorders, 55 (18.4%) had chromosomal
abnormalities, 10 (3.4%) were due to teratogens and 58 (19.5%) were sporadic. The
remaining 362 (54.8%) patients were found to have no disorder of genetic or known
environmental cause (Tables 2 and 3).
Autosomal recessive disorders
Table 4 shows the classification of the 100 patients with autosomal recessive disorders.
Group I consisted of 32 patients (4.8%) with metabolic defects. Among those, 22 patients
(3.3%) had aminoacidopathies and 10 (1.5%) had mucopolysaccharidoses. Group II
consisted of 18 patients (2.7%) with haemoglobinopathies. Of these, 10 (1.5%) had bthalassaemia major and 8 (1.2%) had sickle-cell anemia. Group III consisted of 50 patients
(7.6%) with syndromes and single defects. Microcephaly, with or without spastic quadriplegia,
congenital deafness and spinal muscle atrophy (infantile and juvenile) were the most common
conditions in this group (Table 5). The rare specific syndromes are also shown in Table 5.
Family history
Affected siblings were found in 18 (56.3%) families with metabolic defects. Of those patients
with haemoglobinopathies, 12 (66.7%) had affected siblings. In group III, affected siblings
were found in one patient with xeroderma pigmentosa, one with ataxia-telangectasia, one with
multiple pterygium syndrome, two cases with microcephaly and all cases with deafness. A
positive family history was present in one case of ectodermal dysplasia and in all cases with
spinal muscle atrophy and Robinow syndrome (Table 4).
Consanguinity and inbreeding coefficient
Table 6 shows that parental consanguinity was 60% among cases with autosomal recessive
disorders (48% for first cousin). This value was significantly higher than that of the general
population (28.9%) (c2 = 32.9, P < 0.01). Parental consanguinity was 68.8% among cases
with metabolic defects, 66.7% among cases with haemoglobinopathies and 52% among
syndromes and single defects. These values were significantly higher than those of the
general population.(c2 = 22.4, 15.7 and 12.8 respectively, P < 0.01).
The average inbreeding coefficient in the genetic disorders is shown in Table 7.
Discussion
A study similar to ours conducted in Kuwait amongst 1300 patients referred to general
genetics clinics showed that 32% of the total referred cases were autosomal recessive, 30%
had chromosomal abberations, 13% had known multifactorial and polygenic disorders, 8%
had autosomal dominant disorders, 2% had X-linked disorders and 15% had unknown
disorders [4]. In our study, 45.2% of the patients had genetic defects. This figure is higher
than that reported in a similar study by Devi et al (15.5%) in India [5], but Arabs appear to
have a high frequency of genetic disorders and in particular autosomal recessive traits [4].
The frequency of single gene disorders in this study was 53.7%. This value is lower than that
reported by Devi et al (63.5%) [5] and Teebi (57%) [4]. However, it is higher than that reported
by Hoodfar and Teebi (32.5% among cases of Middle Eastern origin) [6]. This might be due to
differences in the level of consanguineous marriage and the geographical distribution among
these populations.
The frequency of autosomal recessive disorders in our study was 33.6%. This is lower than
that reported by Devi and colleagues (38.1%) [5] and Teebi (45%) [4], but higher than that
reported by Hoodfar and Teebi (14.5%) in a Middle Eastern population in a western city [6].
This is probably related to consanguinity.
Metabolic disorders are individually rare but collectively numerous with wide variations in their
frequencies among cases with mental retardation in different surveys. Wuu et al. reported
0.5% metabolic defects among 1248 cases with mental retardation in Taiwan [7]. Henderson
et al. reported a frequency of 0.6% in a survey of 1087 cases with mental retardation in South
Africa [8]. Tayel et al. found a frequency of 22% in children in Egypt [9]. In the present study
the frequency was 4.8%. This value is lower than that reported by Devi and colleagues (6.4%)
[5]. These variations could be due to the selection of the cases referred.
Aminoacidopathies are one of the major causes for psychomotor retardation [2]. Their
frequency among mentally retarded patients varies from 2.5% to 39% in different studies [912]. In the present study it was 2.7%. This value agrees with the result reported by Devi et al.
(2.7%) [5]. Mucopolysaccharidoses (MPS) are a group of inherited disorders of metabolism
with varying clinical manifestations [13]. There are wide variations in the frequency of MPS
among mentally retarded children as reported by different researchers [14-16]. Piraud et al.
studied 2000 patients in France and found MPS in 170 cases (8.5%) [14], Di Natale et al.
evaluated 297 patients in Italy and found MPS in 147 cases (16.2%) [15] and Michelakakis et
al. studied 2745 patients in Greece and found MPS in 36 cases (1.3%) [16]. In the present
study, MPS was detected in 1.5% of cases while Devi et al. reported a frequency of 1%
among 407 cases included in their study [5].
There is considerable ethnic and geographical variation in the incidence, frequency and
distribution of haemoglobin disorders [17]. Thalassaemia, sickle-cell anaemia and glucose-6phosphate dehydrogenase (G6PD) deficiency are the commonest single gene disorders
encountered in the Eastern Mediterranean Region. The epidemiology of these disorders
shows marked intracountry as well as intercountry differences. The percentage of bthalassaemia trait ranges from 1% to 6% in the Eastern Mediterranean Region as assessed
through neonatal screening [17]. Our study found 10 cases (1.5%) with b-thalassaemia major.
The frequency of sickle-cell anaemia is reported to vary between 1.2% and 2.1% among
neonates in the Libyan Arab Jamahiriya [18]. Only 1.2% of patients in our study had sicklecell anaemia.
In the present study, syndromes and single defects constituted 50% of cases with autosomal
recessive disorders. Reports from countries in the Eastern Mediterranean Region have
pointed to higher frequencies of various autosomal recessive syndromes [3]. Microcephaly,
with or without spastic quadriplegia, had a high frequency (12/50, 24%). Microcephaly without
spasticity is the uncomplicated autosomal recessive type. Microcephaly with seizures and
spasticity was the most common type of genetic microcephaly reported by Tolmie et al. in
Scotland [19], which is what we found in our study.
Congenital deafness was a relatively common condition found in this study (5/50; 10%).
Deafness has a remarkable genetic heterogeneity [20]. The presence of consanguinity and
more than one affected member in the family indicates an autosomal recessive type of
congenital deafness.
The age of onset is the main feature which distinguishes the infantile and juvenile types of
spinal muscle atrophy. In this study, the infantile type (5/50, 10%) was more frequent than the
juvenile (2/50, 4%). This could be due to the early onset of manifestations in the infantile type.
All cases had a family history of the disease.
Xeroderma pigmentosa (XP), Fanconi anaemia (FA) and ataxia-telangectasia (AT) are a
group of autosomal recessive disorders (chromosomal breakage syndromes), characterized
by defective DNA repair and increased chromosomal breaks [2]. XP is the commonest of
these disorders and the most intensively studied [2]. In the present study, XP was more
frequent (4/9, 44.4%) than other types of chromosomal breakage syndromes (FA: 3/9, 33.3%
and AT: 2/9, 22.2%) and this concurs with previous reports [2, 21].
Although sex-linked inherited ectodermal dysplasia is the most common type, a rare
autosomal recessive form of anhydrotic or hypohydrotic ectodermal dysplasia exists [20]. In
this work two patients had the autosomal recessive type of ectodermal dysplasia.
A recessive type of multiple pterygium syndrome was reported in the present study. Several
cases have been reported and all had consanguineous parents [20,22], which was also found
in our study.
Retinitis pigmentosa unassociated with other abnormalities is inherited most frequently as an
autosomal recessive disorder. In our study, two patients were diagnosed as autosomal
recessive retinitis pigmentosa.
Friedreich ataxia is one of the rare spinocerebellar degenerative disorders. We found two
patients with this disorder.
Two patients were diagnosed with optic atrophy. Autosomal recessive congenital optic
atrophy is very rare. The profound bilateral vision loss is stable and usually associated with
nystagmus [23]. Parental consanguinity has been found in 50% of the cases [23]. Our findings
concur with this.
Spastic paraplegia is a relatively non-specific manifestation. A recessively inherited spastic
paraplegia is rare [20]. Two patients with spastic paraplegia were detected in the present
study.
Other syndromes and diseases were less frequent and represented by one patient (Table 5).
Bardet-Biedl syndrome is differentiated from Laurence Moon syndrome by the presence of
polydactyly, obesity and the absence of spastic paraplagia [20]. Carpenter syndrome is a rare
autosomal recessive acrocephalopoly syndactyly [29]. Robinow syndrome is usually a
dominant disease [20], but a rare recessive form is suggested by the reports of Saal et al.
[24]. The patient in this study had a positive history, two siblings affected and the parents
were consanguineous. SHORT syndrome is characterized by short stature, hyperextensibility
of joints, ocular depression, Rieger anomaly and teething delay. It is inherited as an
autosomal recessive disorder [20]. Diastrophic dysplasia is a form of dwarfism associated
with clubbed feet, malformed pinna, calcification of cartilage and hitchhiker thumb [20]. These
characteristics were found in the patient in our study.
Consanguineous mating is genetically important as closely related individuals have a higher
chance of carrying the same alleles than unrelated individuals; hence the offspring of
consanguineous mating are more frequently homozygous for various alleles than those from
other unions [1].
The rate of consanguinity among parents of patients with autosomal recessive disorders in
the present study was higher (60%) than that of the general population in Egypt (28.9%) [25].
This concurs with Hoodfar and Teebi who found that autosomal recessive disorders were
more than twice as common in inbred families than in non-inbred ones [6]. The rate of firstcousin marriages was high (48%) when compared with 14% in the general population [25].
This is in agreement with the findings of Roberts and Pembry in a Middle East sample [26]
and Orioli et al. in a South American sample [27]. In addition, the consanguinity level was
highest in the autosomal recessive group when compared with other genetic conditions in our
study (Tables 6 and 7). Autosomal recessive disorders have a high risk of recurrence. This
was evident in the present study as 49% of the patients had a positive family history (33%
had positive consanguinity and 16% were non-consanguineous). This illustrates the role of
consanguinity in increasing the incidence of autosomal recessive diseases in a population.
The average coefficient of inbreeding in cases with autosomal recessive diseases was found
to be high (0.03), which is almost triple that of the Egyptian population in general (0.01) [25].
Inbreeding in itself is not responsible for the appearance of unfavourable phenotypes.
However, it tends to reveal deleterious recessive alleles present in heterozygous carriers and
hence consanguinity will lead to increased frequencies of homozygotes for rare alleles [1].
Conclusion
An understanding of the factors influencing the genetic disease profile of a population is
important. Our study found that the frequency of genetic disorders among cases referred to
our clinic was 45.2%. Autosomal recessive diseases accounted for 33.6% of these disorders.
Consanguinity and the average inbreeding coefficient among parents of patients with
autosomal recessive disorders were high (60% and 0.03 respectively). These findings are
crucial for geneticists and genetic counsellors in their evaluation, diagnosis, counselling and
management of patients.
Acknowledgements
We would like to thank all members of the Human Genetics Department for their cooperation
and efforts.
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